Racemic Peptides from Amyloid ß and Amylin Form Rippled ß-Sheets Rather Than Pleated ß-Sheets.

The rippled ß-sheet was theorized by Pauling and Corey in 1953 as a structural motif in which mirror image peptide strands assemble into hydrogen-bonded periodic arrays with strictly alternating chirality. Structural characterization of the rippled ß-sheet was limited to biophysical methods until 2022 when atomic resolution structures of the motif were first obtained. The crystal structural foundation is restricted to four model tripeptides composed exclusively of aromatic residues. Here, we report five new rippled sheet crystal structures derived from amyloid ß and amylin, the aggregating toxic peptides of Alzheimer's disease and type II diabetes, respectively. Despite the variation in peptide sequence composition, all five structures form antiparallel rippled ß-sheets that extend, like a fibril, along the entire length of the crystalline needle. The long-range packing of the crystals, however, varies. In three of the crystals, the sheets pack face-to-face and exclude water, giving rise to cross-ß architectures grossly resembling the steric zipper motif of amyloid fibrils but differing in fundamental details. In the other two crystals, the solvent is encapsulated between the sheets, yielding fibril architectures capable of host-guest chemistry. Our study demonstrates that the formation of rippled ß-sheets from aggregating racemic peptide mixtures in three-dimensional (3D) assemblies is a general phenomenon and provides a structural basis for targeting intrinsically disordered proteins.

The rippled ß-sheet layer configuration-a novel supramolecular architecture based on predictions by Pauling and Corey.

The rippled ß-sheet is a peptidic structural motif related to but distinct from the pleated ß-sheet. Both motifs were predicted in the 1950s by Pauling and Corey. The pleated ß-sheet was since observed in countless proteins and peptides and is considered common textbook knowledge. Conversely, the rippled ß-sheet only gained a meaningful experimental foundation in the past decade, and the first crystal structural study of rippled ß-sheets was published as recently as this year. Noteworthy, the crystallized assembly stopped at the rippled ß-dimer stage. It did not form the extended, periodic rippled ß-sheet layer topography hypothesized by Pauling and Corey, thus calling the validity of their prediction into question. NMR work conducted since moreover shows that certain model peptides rather form pleated and not rippled ß-sheets in solution. To determine whether the periodic rippled ß-sheet layer configuration is viable, the field urgently needs crystal structures. Here we report on crystal structures of two racemic and one quasi-racemic aggregating peptide systems, all of which yield periodic rippled antiparallel ß-sheet layers that are in excellent agreement with the predictions by Pauling and Corey. Our study establishes the rippled ß-sheet layer configuration as a motif with general features and opens the road to structure-based design of unique supramolecular architectures.

Palladium-catalyzed substitution of allylic fluorides.

As unusual substrates for the Tsuji-Trost allylation reaction, allylic fluorides are responsive to palladium-catalyzed substitution. Their activity towards this reaction fits in the series OCO(2)Me>OBz>>F>>OAc. The classic stereoretention mechanism that involves sequential inversions does not operate in this case. Several distinct cases are considered.